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Study of the effects of DNA demethylation on genes associated with developmental pathways in pediatric Ependymomas

Grant number: 18/23372-4
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2019
Effective date (End): August 31, 2022
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Luiz Gonzaga Tone
Grantee:Graziella Ribeiro de Sousa
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:14/20341-0 - Interactions between emerging therapeutic targets and developmental pathways associated with tumorigenesis: emphasis on pediatric malignancies, AP.TEM

Abstract

Ependymoma (EPN) is a primary neuroepithelial Central Nervous System (CNS) tumor originated in ependymal cells. It is the third most frequent of CNS tumor in childhood and corresponds to 6 to 12% of pediatric intracranial tumors. Currently, the treatment is performed with surgical resection and radiotherapy. Clinical trials with chemotherapy have been performed, but have not shown promising results. Since approximately 40% of the tumors are incurable and 50% of the patients develop local recurrence, the investigation of new therapeutic targets is necessary. In this context, the developmental molecular alterations such as Wnt, Hh and Notch, which have been described as responsible for the maintenance of auto-renewal of cancer cells in EPN. In addition to genetic modifications, epigenetic changes play an important role in the control of these pathways, such as silencing by hypermethylation of negative regulators. However, there are few reports that detail these mechanisms in EPN. Epigenetic modifications can be reversed, it has been demonstrated that the application of DNA methyltransferase inhibitors (DNMTs), such as 5-azacytidine, has shown antineoplastic effects in EPN, and is in phase I clinical trials. However, its use in different tumor types resulted in high toxicity for the patients. In this sense, second-generation cytidine analogues such as zebularine have been developed which present greater bioavailability, stability and less effects in non-tumor cells. The purpose of the present project is to verify the functional and molecular effects of zebularin in EPN cell lines, especially in regulator genes of developmental pathways in subgroups of worse prognosis, with the potential to provide a better understanding of mechanisms inherent to this tumor and to identify alternative therapies targeting cancer-specific epigenetic patterns. (AU)